At the heart of it… why quaternary diaphragm pumps are ideal for biopharma manufacturing

In this article, Glenn Hiroyasu, Americas development manager for Quattroflow Fluid Systems, examines the challenges of flow rate and pressure in chromatography, virus filtration, TFF and inline blending processes and illustrates why the quaternary diaphragm pump is ideal for use in biopharmaceutical-manufacturing applications.

Every iteration of unit operation in biopharmaceutical manufacturing must adhere to an unbending set of operational parameters if the desired outcome — a viable, contaminant-free drug suitable for human or animal consumption and administration — is to be realised.

Four of the more common unit operations within the biopharmaceutical-manufacturing universe are chromatography, virus filtration, tangential flow filtration (TFF) and inline blending. For these operations to be implemented successfully, though, the operator must be aware of their specific operating characteristics, all of which revolve around fluid transfer.

The unit operations — a closer look

Chromatography columns

Chromatography columns contain complex target-product adsorbing media that need careful handling. Protein A resin, for example, can cost as much as $10,000 a litre, making proper feeding of the resin extremely important.

Some chromatography systems require buffer gradients to achieve purification of the proteins. Quite often more than one buffer is required, which creates the need to use two or more pumps. Because of this, precise pumping is required to achieve the right pH/conductivity conditions for specific adsorption and high-resolution purification.

Virus filtration

Virus-filtration systems are used to ensure the viability and safety of the drugs that are produced through the removal of potential contaminants from products that are created using cell cultures. The operation of most virus-filtration systems use constant pressures with variable flows.

These flows change as the virus filter becomes clogged. When this happens, the flow rate will not decrease in a linear fashion, which will adversely affect the performance of the filter, product yield and overall quality.

TFF

Also known as cross-flow filtration, in TFF the biologic feed stream flows tangentially across the filter membrane at positive pressure. As it passes across the membrane, the portion of the feed stream that is smaller than the membrane’s pore size passes through the membrane.

TFF is different from what is known as normal-flow (NFF), or ‘dead-end’, filtration because the tangential motion of the fluid across the membrane prevents molecules from building up a compact gel layer on the surface of the membrane. This mode of operation means that a TFF process can operate continuously with relatively high protein concentrations with less fouling or binding of the filter.

Inline blending

Also known as continuous blending or inline mixing, inline blending systems create a new standard for just-in-time-production and reflect the next step in the evolution of continuous-production technology. In this process, liquid ingredients are fed proportionally to one main stream and are instantly mixed since they are being transferred within a common manifold.

To obtain exactly the right product, this process requires good metering and volumetric efficiency capabilities that can facilitate the automation of the system. When this inline blending is continuous, the blending is instantaneous and there is no space or time available for corrections.

The ‘pump’ challenge

Various pump technologies have been tested and used for the common unit operations. Two of the more popular are lobe and peristaltic (hose) pumps. Both, however, feature operational inefficiencies that may make them insufficient for use.

Lobe pumps

Since many biopharmaceutical materials are contained in a low-viscosity aqueous solution, lobe pumps may not be a good choice because slippage can occur during their operation. Slip will also result in increased shear damage and energy consumption, and if used in a TFF filtration system, there can be noticeable heat addition to the product that requires significant cooling efforts to protect the product from overheating.

Lobe pumps also have mechanical seals, which do not provide full containment unless special (and oftentimes expensive) seals and seal barriers are used. The sterility required in biopharmaceutical handling means that no outside contaminants can be introduced into the purification process, which is something that pumps with mechanical seals cannot reliably ensure.

Finally, the necessary contact between a lobe pump’s internal parts can lead to wear and the generation of particles that can result in product contamination. Solid particulates can also cause severe damage to the lobes, resulting in damage to the entire product batch.

Peristaltic (hose) pumps

The obvious shortcoming of peristaltic pumps is their method of operation, which will undoubtedly produce pulsation — an undesirable in biopharmaceutical manufacturing. Peristaltic pumps also have limited flow and pressure-handling abilities.

They can also release some small quantity of hose material — in a process known as ‘spalling’ — into the pumped product, which can compromise its purity. If the spalled hose material makes its way to the filter, it can foul the filter, making its operation less efficient than required, which will also lead to contamination.

In the end, the shortcomings of lobe and peristaltic pumps come down to two main things:

• If there is shear, which is common in lobe pumps, you will damage the pumped material
• If there is pulsation, a certainty with peristaltic pumps, you won’t have even flow, which means you won’t have accurate flow

The solution

An effective counter to the operational shortcomings of lobe and peristaltic pumps can be the quaternary diaphragm pump.

In 1986, Frank Glabiszewski was an engineer for a German filter manufacturer who was growing increasingly frustrated with the operation of the pumping technologies that were commonly used in chromatography and TFF applications.

His search for a solution led him to consider the operation of the human heart. With that vision in mind, Glabiszewski and his engineering partner, Josef Zitron, invented the quaternary (four-piston) diaphragm pump technology. As the use of quaternary pumps has increased, the technology has been modified (disposable plastic heads and wetted parts) to make it applicable in the burgeoning single-use biopharmaceutical-production marketplace.

The four-piston diaphragm technology creates a gentle pumping action through soft ‘heartbeats’, producing four overlapping pumping strokes of the pistons that efficiently reduce pulsation.

The method of operation allows it to gently, safely and securely convey low-viscosity aqueous solutions and biopharmaceutical materials that are highly sensitive to shear forces and pulsation while being pumped.

Of course, not every pump technology is completely perfect for every fluid-handling application. In this instance, the design and operation of the quaternary diaphragm pump limits it to handling fluids that have a maximum viscosity of 1,000 centipoise and that contain particulates up to 0.1 mm in diameter.

Conclusion

The importance of biopharmaceuticals means that any and all products must meet strict demands regarding their manufacture, with no damage to component materials during critical chromatography, virus-filtration, TFF or inline-blending operations. While lobe and peristaltic pumps have been popular for these unit operations, a better choice is the quaternary diaphragm pump, which greatly reduces the chance that pulsation and shear will compromise the safety and effectiveness of the final product.